Overall objective: Develop and implement treatment planning approaches for optimizing radio-immunotherapy (RIT). The emphasis during the first period of funding was on developing analytical tools for achieving this objective. The emphasis in this application is on applying these tools in the analysis and optimization of novel and emerging RIT. Specific Aims: 1. Calculate the expected therapeutic impact of prescribing, for each patient, the amount of unlabeled (cold) antibody (Ab) given in RIT of non-Hodgkin's Lymphoma; define a protocol for obtaining the optimum amount. 2. Using models of normal tissue histology for microdosimetry calculations, estimate expected normal tissue toxicity with alpha- emitter RIT; predict appropriate dose-escalation schedules for alpha- emitter RIT for minimal disease. 3. Continue support and development of techniques and software related to 3-D and patient-specific internal dosimetry. Background & Methods: 1. 131I-anti-Bl Ab has yielded durable complete responses in patients with otherwise untreatable non-Hodgkin's Lymphoma/ Currently, 131I-anti-Bl is preceded by a fixed amount of cold anti-Bl for all patients. This is thought to improve targeting by saturating rapidly accessible, non-tumor antigen sites. Total tumor burden will be estimated from CT and SPECT of 131I-anti-Bl patients. Absorbed dose and dose volume-histograms of several index tumors will be calculated to evaluate correspondence with response. Retrospective analyses will be conducted to see if "underdosing" (too little Ab relative to tumor burden) led to reduced response and "overdosing" to increased toxicity. 2. Alpha emitters are ideal for eradicating minimal or micrometastatic disease due to their short range and high energy. These properties also make it difficult to predict normal organ toxicity. Mathematical models of organ histology will be developed and used for microdosimetry calculations to evaluate toxicity in RIT trials directed against micrometastases. 3. The dosimetery methodologies developed under this grant have been implemented in a software package called 3D-ID (3d-Internal Dosimetry). This software has been provided to, and used by, several outside investigators in on-going collaborations. Aim 3 will make it possible to continue upgrading and adding features to this software and also to continue investigating new, dosimetry-related, techniques for treatment planning. Summary: Completion of the aims will (1) markedly improve what is likely to become a prevalent therapy for Non-Hodgkin's Lymphoma and (2) will provide fundamental information for designing clinical trials of a novel and emerging approach for eradicating minimal disease.